Production of N-substituted 2,7-dialkyl-4-hydroxy-5-amino-8-arly-octanoylamides
View Patent ↗From compounds of formula II wherein R 1 and R 2 are independently of one another H, C 1 –C 6 alkyl, C 1 –C 6 halogenalkyl, C 1 –C 6 alkoxy, C 1 –C 6 alkoxy-C 1 –C 6 alkyl, or C 1 –C 6 alkoxy-C 1 –C 6 alkyloxy, R 3 is C 1 –C 6 alkyl, R 4 is C 1 –C 6 alkyl, and R 5 is C 1 –C 6 alkyl, C 1 –C 6 hydroxyalkyl, C 1 –C 6 alkoxy-C 1 –C 6 -alkyl, C 1 –C 6 alkanoyloxy-C 1 –C 6 alkyl, C 1 –C 6 aminoalkyl, C 1 –C 6 alkylamino-C 1 –C 6 -alkyl, C 1 –C 6 -dialkylamino-C 1 –C 6 -alkyl, C 1 –C 6 -alkanoylamido-C 1 –C 6 -alkyl, HO(O)C—C 1 –C 6 -alkyl, C 1 –C 6 alkyl-O—(O)C—C 1 –C 6 alkyl, H 2 N—C(O)—C 1 –C 6 alkyl, C 1 –C 6 alkyl-HN—C(O)—C 1 –C 6 alkyl or (C 1 –C 6 alkyl) 2 N—C(O)—C 1 –C 6 -alkyl, R 6 is C 1 –C 6 alkyl, R 7 is C 1 –C 6 alkyl or C 1 –C 6 alkoxy, or R 6 and R 7 together are tetramethylene, pentamethylene, 3-oxa-1,5-pentylene or —CH 2 CH 2 O— substituted, if necessary, with C 1 –C 4 -Alkyl, phenyl or benzyl, it is possible—through halolactonization, azidation of the halogen group, ring opening with an amine R 5 —NH 2 , and reduction of the azide group to form the amino group—to prepare compounds of formula I wherein R 5 is C 1 –C 6 alkyl, C 1 –C 6 hydroxyalkyl, C 1 –C 6 alkoxy-C 1 –C 6 alkyl, C 1 –C 6 alkanoyloxy-C 1 –C 6 alkyl, C 1 –C 6 aminoalkyl, C 1 –C 6 alkylamino-C 1 –C 6 alkyl, C 1 –C 6 dialkylamino-C 1 –C 6 -alkyl, C 1 –C 6 alkanoylamido-C 1 –C 6 alkyl, HO(O)C—C 1 –C 6 alkyl, C 1 –C 6 alkyl-O—(O)C—C 1 –C 6 alkyl, H 2 N—C(O)—C 1 –C 6 alkyl, C 1 –C 6 alkyl-HN—C(O)—C 1 –C 6 alkyl or (C 1 –C 6 alkyl) 2 —N—C(O)—C 1 –C 6 alkyl. If 2(S), 7(R)-diastereomer of formula II is used, the 2(S), 4(S), 5(S), 7(S)-diastereomer of formula Ia is obtained in a high degree of purity.
1. Process for preparation of compounds of formula I,
wherein
R 1 and R 2 are independently of one another H, C 1 –C 6 alkyl, C 1 –C 6 halogenalkyl, C 1 –C 6 alkoxy, C 1 –C 6 alkoxy-C 1 –C 6 alkyl, or C 1 –C 6 alkoxy-C 1 –C 6 alkyloxy, R 3 is C 1 –C 6 alkyl, R 4 is C 1 –C 6 alkyl, and R 5 is C 1 –C 6 alkyl, C 1 –C 6 hydroxyalkyl, C 1 –C 6 alkoxy-C 1 –C 6 -alkyl, C 1 –C 6 alkanoyloxy-C 1 –C 6 alkyl, C 1 –C 6 aminoalkyl, C 1 –C 6 alkylamino-C 1 –C 6 -alkyl, C 1 –C 6 -dialkylamino-C 1 –C 6 -alkyl, C 1 –C 6 -alkanoylamido-C 1 –C 6 -alkyl, HO(O)C—C 1 –C 6 -alkyl, C 1 –C 6 alkyl-O—(O)C—C 1 –C 6 alkyl, H 2 N—C(O)—C 1 –C 6 alkyl, C 1 –C 6 alkyl-HN—C(O)—C 1 –C 6 alkyl or (C 1 –C 6 alkyl) 2 N—C(O)—C 1 –C 6 -alkyl, comprising
a) the reaction of a compound of formula II
wherein
R 6 is C 1 –C 6 alkyl, R 7 is C 1 –C 6 alkyl or C 1 –C 6 alkoxy, or R 6 and R 7 together are tetramethylene, pentamethylene, 3-oxa-1,5-pentylene or —CH 2 CH 2 O—C(O)— optionally substituted with C 1 –C 4 alkyl, phenyl or benzyl, with a halogenation agent in the presence of water, and optionally, an acid to form a compound of formula III,
wherein X is Cl, Br or I,
b) reaction of the compound of formula III with an azidation agent to form a compound of formula IV,
c) thereafter reaction of the compound of formula IV with an amine of formula R 5 —NH 2 to form a compound of formula V,
and
d) for preparation of a compound of formula I, reduction of the azide group of the compound of formula V to form the amine group and then isolation of the compounds of formula I, optionally with the addition of a salt-forming acid.
2. A process according to claim 1 wherein R 1 is C 1 –C 4 alkoxy or C 1 –C 4 alkoxy-C 1 –C 4 alkyloxy, R 2 is C 1 –C 4 alkoxy, R 3 is C 1 –C 4 alkyl, R 4 is C 1 –C 4 alkyl and R 5 is H 2 NC(O)—C 1 –C 6 alkyl which optionally is N-monosubstituted or N-di-C 1 –C 4 alkyl substituted.
3. A process according to claim 2 wherein R 1 is 1-methoxyprop-3-yloxy and R 2 is methoxy.
4. A process according to claim 2 wherein R 3 and R 4 are in each case isopropyl.
5. A process according to claim 2 wherein R 5 is H 2 NC(O)—C 1 –C 6 alkyl.
6. A process according to claim 1 wherein R 1 is methoxy-C 2 –C 4 alkyloxy, R 2 is methoxy or ethoxy, R 3 is C 2 –C 4 alkyl, R 4 is C 2 –C 4 alkyl and R 5 is H 2 NC(O)—C 1 –C 6 alkyl.
7. A process according to claim 1 wherein R 1 is 3-methoxy-prop-3-yloxy, R 2 is methoxy, R 3 and R 4 are 1-methyleth-1-yl, and R 5 is H 2 NC(O)-[C(CH 3 ) 2 ]—CH 2 —.
8. A process according to any one of claims 1 to 7 comprising the preparation of diastereomers of formula Ia
by
a) the reaction of a compound of formula IIa
with a halogenation agent in the presence of water and optionally an acid to form a compound of formula IIIa,
wherein X is Cl, Br or I,
b) reaction of the compound of formula IIIa with an azidation agent to form a compound of formula IVa,
c) then reaction of the compound of formula IVa with an amine of formula R 5 —NH 2 to form a compound of formula Va,
and
d) for preparation of a compound of formula I, reduction of the azide group of the compound of formula Va to form the amine group and then isolation of the compounds of formula Ia, optionally with the addition of a salt-forming acid.
9. A process according to claim 8 , wherein R 1 is CH 3 O—(CH 2 ) 3 —O—, R 2 is CH 3 O—, R 3 and R 4 are in each case 1-methylethyl, and R 5 is —CH 2 —(CCH 3 ) 2 —C(O)—NH 2 .